US20210386761A1 - Composition for preventing or treating inflammatory bowel disease, containing, as active ingredient, taurodeoxycholic acid or pharmaceutically acceptable salt thereof - Google Patents

Composition for preventing or treating inflammatory bowel disease, containing, as active ingredient, taurodeoxycholic acid or pharmaceutically acceptable salt thereof Download PDF

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US20210386761A1
US20210386761A1 US17/284,305 US202017284305A US2021386761A1 US 20210386761 A1 US20210386761 A1 US 20210386761A1 US 202017284305 A US202017284305 A US 202017284305A US 2021386761 A1 US2021386761 A1 US 2021386761A1
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bowel disease
inflammatory bowel
tdca
dss
taurodeoxycholic acid
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Seung-yong Seong
Sang-Uk Seo
Bolormaa MUNKHBILEG
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Shaperon Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/32—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the digestive tract
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to a composition for prevention or treatment of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient, more specifically to a pharmaceutical composition or a health food for prevention or treatment of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Inflammatory bowel disease is a disease causing chronic and unexplained inflammation in the bowels and can be clinically classified into ulcerative colitis and Crohn's disease.
  • Ulcerative colitis is a disease in which sores (erosion) or persistent inflammation is continuously formed in the mucous membrane of the large bowel and ulcers that affect the mucosal epithelium and lamina intestinal of the colon and rectum are continuously formed. 95% of ulcerative colitis affects the rectum and spreads continuously and circumferentially to the closer part of the large bowel. Symptoms of ulcerative colitis include abdominal pain, bloody stool, spots, and diarrhea, and systemic symptoms such as fever, body weight loss, and anemia are caused in severe cases. Ulcerative colitis develops from teens to young adults, occurs at all ages, and affects men and women equally. In recent years, as the incidence rate of ulcerative colitis has increased worldwide, the importance thereof has increased.
  • ulcerative colitis The incidence rate of ulcerative colitis is the highest in the Western world and is estimated to be 30 per 100,000 people. According to the Asia-Pacific Crohn and Colitis epidemiological study, the incidence rate of ulcerative colitis in Asia and the Middle East was 6.3 per 100,000 people on the average in 2012, and this means that the incidence rate of ulcerative colitis in Asia and the Middle East has increased dramatically. In Korea, the incidence rate of ulcerative colitis has increased from 0.22 per 100,000 people in 1886 to 3.62 per 100,000 people after 2005. Ulcerative colitis is a chronic disease that affects the quality of life, is a disease that is financially expensive, and may lead to death if not treated properly.
  • Crohn's disease is a disease in which lesions such as ulcers are discontinuously formed in any part of the digestive tract from the mouth to the anus, and symptoms such as fever, body weight loss, general malaise, and anemia are caused in severe cases in addition to abdominal pain, diarrhea, and bloody stool.
  • sulfasalazine that is frequently used as an aminosalicylic acid preparation, has been reported to have side effects such as nausea, vomiting, loss of appetite, rash, headache, liver injury, leukocytopenia, abnormal red blood cells, proteinuria, and diarrhea.
  • Prednisolone that is an adrenal cortical steroid is used by oral administration, enema, suppository, intravenous injection and the like but has strong side effects such as gastric ulcer or necrosis of the femoral head due to long-term use.
  • Biological therapeutic agents such as TNF- ⁇ monoclonal antibodies have advantages of predicting, preventing, and treating complications in patients, restoring nutritional deficiencies, and reducing mortality but have problems such as high cost and susceptibility to infection in some patients, side effects, and occurrence of low-responders. Hence, in the treatment of inflammatory bowel disease, a new therapeutic agent with a high efficiency but few side effects is required.
  • bile acid is an important physiological molecule in the secretion of bile for absorption of lipids, harmful metabolites, and nutrients in the bowels and is produced in perivenous hepatocytes of human liver.
  • the primary bile acids formed in the human body are chenodeoxycholic acid and cholic acid. Chenodeoxycholic acid is conjugated with taurine or glycine to produce a total of eight conjugated bile acids such as taurochenodeoxycholate and glycochenodeoxycholate.
  • Deoxycholic acid, lithocholic acid, ursodeoxycholic acid and the like are formed as secondary bile acids by the influence of intestinal microbes on the primary bile acids.
  • Cholic acid is converted to deoxycholic acid and chenodeoxycholic acid is converted to lithocolinic acid or ursodeoxycholic acid.
  • Taurine is conjugated to deoxycholic acid to form taurodeoxycholic acid.
  • These bile acids are known to play an important role as signaling molecules in the absorption of dietary lipids and in the regulation of cholesterol homeostasis and systemic endocrine function and to regulate immune homeostasis, intestinal circulation, and metabolism by activating various signal transduction pathways, and are thus applied as therapeutic agents.
  • ursodeoxycholic acid that is present in a significantly small amount as a secondary bile acid has proven its pharmacological effect in improvement of the liver function and is applied as a therapeutic agent for liver disease.
  • the present inventors have tried to develop a new therapeutic agent which exhibits excellent therapeutic effect on inflammatory bowel disease, is safe, and has few side effects and, as a result, confirmed that the clinical symptoms and histopathological symptoms caused by inflammatory bowel disease are alleviated and the increase in inflammatory cells in bowels and the production of pro-inflammatory cytokines are suppressed by using a salt of taurodeoxycholic acid, found that taurodeoxycholic acid and a pharmaceutically acceptable salt thereof can be used as an active ingredient of a composition for prevention or treatment of inflammatory bowel disease, and thus completed the present invention.
  • An object of the present invention is to provide a composition for prevention, treatment, or improvement of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preventing, improving, or treating inflammatory bowel disease, which includes administering a pharmaceutically effective amount of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.
  • Still another object of the present invention is to provide the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a composition for prevention, treatment, or improvement of inflammatory bowel disease.
  • the present invention provides a pharmaceutical composition for prevention or treatment of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a health food for prevention or improvement of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for preventing or improving inflammatory bowel disease, which includes administering a pharmaceutically effective amount of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.
  • the present invention also provides a method for treating inflammatory bowel disease, which includes administering a pharmaceutically effective amount of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.
  • the present invention also provides the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for prevention or treatment of inflammatory bowel disease.
  • the present invention also provides the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a health food for prevention or improvement of inflammatory bowel disease.
  • the present inventors have confirmed that the clinical symptoms and histopathological symptoms caused by inflammatory bowel disease are alleviated and the increase in inflammatory cells in bowels and the production of pro-inflammatory cytokines are suppressed by using a salt of taurodeoxycholic acid, and thus taurodeoxycholic acid and a pharmaceutically acceptable salt thereof can be used as an active ingredient of a composition for prevention or treatment of inflammatory bowel disease.
  • FIGS. 1A to 1C are diagrams illustrating the clinical symptoms-alleviating effect by sodium taurodeoxycholic acid (TDCA) in a mouse model in which inflammatory bowel disease is induced by administration of dextran sodium sulfate (DSS),
  • FIG. 1A illustrates the body weight change
  • FIG. 1B illustrates the disease activity index (DAI) change
  • FIG. 1C illustrates the survival rate change (*p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001).
  • FIGS. 2A to 2C are diagrams illustrating the histopathological symptoms alleviating-effect by TDCA in a mouse model in which inflammatory bowel disease is induced by administration of DSS
  • FIG. 2A illustrates the colon length change
  • FIG. 2B illustrates the histological state change
  • FIG. 2C illustrates the histological score change (red arrow: inflammatory cell infiltration
  • black arrow mucosal epithelium and intestinal crypt damage).
  • FIGS. 3A to 3B are diagrams illustrating the effect of decreasing inflammatory cells and pro-inflammatory cytokines in the bowels by TDCA in a mouse model in which inflammatory bowel disease is induced by administration of DSS
  • FIG. 3A illustrates the changes in inflammatory cells
  • FIG. 3B illustrates the changes in pro-inflammatory cytokines.
  • FIGS. 4A to 4B are diagrams illustrating the clinical symptoms-alleviating effect depending on the TDCA concentration in a mouse model in which inflammatory bowel disease is induced by administration of DSS, FIG. 4A illustrates the body weight change, and FIG. 4B illustrates the DAI change.
  • FIGS. 5A to 5C are diagrams illustrating the histopathological symptoms-alleviating effect depending on the TDCA concentration in a mouse model in which inflammatory bowel disease is induced by administration of DSS
  • FIG. 5A illustrates the colon length change
  • FIG. 5 B illustrates the histological state change
  • FIG. 5C illustrates the histological score change.
  • FIGS. 6A to 6C are diagrams illustrating the clinical symptoms and pathological symptoms-alleviating effect by TDCA administration before or after DSS administration in a mouse model in which inflammatory bowel disease is induced by administration of DSS
  • FIG. 6A illustrates the body weight change
  • FIG. 6B illustrates the DAI change
  • FIG. 6C illustrates the colon length change.
  • FIGS. 7A to 7B are diagrams illustrating the effect of decreasing inflammatory cells and pro-inflammatory cytokines in the bowels by TDCA administration before or after DSS administration in a mouse model in which inflammatory bowel disease is induced by administration of DSS, FIG. 7A illustrates the changes in inflammatory cells, and FIG. 7B illustrates the changes in pro-inflammatory cytokines.
  • FIGS. 8A to 8C are diagrams illustrating the changes in clinical symptoms by TDCA in a TGR5 knock-out (TGR5 ⁇ / ⁇ ) mouse model in which inflammatory bowel disease is induced by administration of DSS
  • FIG. 8A illustrates the body weight change
  • FIG. 8B illustrates the DAI change
  • FIG. 8C illustrates the survival rate change.
  • FIGS. 9A to 9F are diagrams illustrating the changes in clinical symptoms in a mouse model in which inflammatory bowel disease is induced by administration of DSS in comparison with those by prescription drugs, tofacitinib and 5-ASA (5-acetyl salicylic acid) used in the clinic
  • FIG. 9A illustrates the body weight change
  • FIG. 9B illustrates the DAI change
  • FIG. 9C illustrates the colon length change
  • FIG. 9D illustrates the changes in lesion index of colon tissue
  • FIG. 9E illustrates the changes in pro-inflammatory cytokines in colon tissue
  • FIG. 9F illustrates the representative lesion changes of colon tissue in respective administration groups.
  • FIGS. 10A to 10B are diagrams illustrating the inhibitory ability of TDCA on the secretion of pro-inflammatory cytokines that are important for inducing ulcerative colitis confirmed by isolating and culturing bone marrow-derived macrophages from mice, FIG. 10A illustrates the percentage changes in inhibitory ability depending on the TDCA concentration, and FIG. 10B illustrates the changes in secretion amount of pro-inflammatory cytokine IL-1 ⁇ depending on the TDCA concentration.
  • FIGS. 11A to 11B are diagrams illustrating the changes in clinical symptoms in a mouse model in which chronic inflammatory bowel disease is induced by repeated administration of DSS at regular intervals in comparison with those by prescription drugs, tofacitinib, 5-ASA (5-acetyl salicylic acid), and prednisolone used in the clinic, FIG. 11A illustrates the body weight change, and FIG. 11B illustrates the mortality.
  • the present invention provides a pharmaceutical composition for prevention or treatment of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for prevention or treatment of inflammatory bowel disease.
  • taurodeoxycholic acid those isolated from animal carcasses, for example, animals such as sheep, dogs, goats, or rabbits, commercially available ones, and synthesized ones may be all safely used.
  • the taurodeoxycholic acid is a kind of bile acid, is in the form of taurine-conjugated deoxycholic acid, and has a chemical structure represented by the following [Chemical Formula 1], more specifically a chemical structure represented by the following [Chemical Formula 2]
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can inhibit the production of pro-inflammatory cytokines, more specifically the production of IL-6, IL-1 ⁇ , or TNF- ⁇ .
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can exhibit an equivalent or higher efficacy as compared with tofacitinib, 5-ASA (5-acetyl salicylic acid), and steroid drugs that are all currently used in the clinic for the treatment of ulcerative colitis.
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can decrease the number of inflammatory cells in the bowels.
  • the inflammatory bowel disease may be ulcerative colitis, collagenous colitis, lymphoid colitis, ischemic colitis, convertible colitis, Crohn's disease, Behcet's syndrome, uncertain colitis, hemorrhagic rectal ulcer, or ileal cystitis but is not limited thereto.
  • the present inventors administered sodium taurodeoxycholic acid to a mouse model in which inflammatory bowel disease was induced by administration of dextran sodium sulfate (DSS) before or after the DSS administration, analyzed clinical symptoms and histopathological symptoms, and as a result, confirmed that the clinical symptoms appearing in inflammatory bowel disease-induced mouse model such as body weight loss, diarrhea, and bloody stool and the histopathological symptoms such as a decrease in colon length, infiltration of inflammatory cells into mucous membrane, damage to the intestinal crypt, and ulcer were alleviated by the administration of sodium taurodeoxycholic acid (see FIGS. 1A to 1C, 2A to 2C, and 6A to 6C ).
  • DSS dextran sodium sulfate
  • TDCA body weight change and DAI change
  • the present inventors administered sodium taurodeoxycholic acid to a mouse model in which inflammatory bowel disease was induced by administration of DSS before or after the DSS administration, analyzed the inflammatory cells and pro-inflammatory cytokines, and as a result, confirmed that the increase in inflammatory cells and pro-inflammatory cytokines was suppressed in the intestinal tissue of the inflammatory bowel disease-induced mouse model by the administration of sodium taurodeoxycholic acid.
  • An equivalent effect was confirmed in IL-6 and TNF- ⁇ inhibition and an equivalent or higher effect was confirmed in IL-1 ⁇ inhibition as compared with those by the clinical prescription drugs, tofacitinib and 5-ASA (see FIGS. 3A to 3B, 4A to 4B, 7A to 7B, and 9A to 9F ).
  • the present inventors administered sodium taurodeoxycholic acid at different concentrations to a mouse model in which inflammatory bowel disease was induced by administration of DSS, analyzed clinical symptoms and histopathological symptoms, and as a result, confirmed that superior effects were exhibited when sodium taurodeoxycholic acid was administered at an administration concentration of 2.5 to 10 mg/kg (see FIGS. 5A to 5C, and 6A to 6C ).
  • TDCA-administered group exhibits an equivalent or higher effect when the clinical symptoms (body weight change and mortality) in a mouse model in which chronic inflammatory bowel disease was induced by repeated administration of DSS in the case of TDCA 2.5 mg/kg BID (administered two times a day) or TDCA 2.5 mg/kg TID (administered 3 times a day) were compared with those in the case of clinical prescription drugs (see FIGS. 11A to 11B ).
  • TDCA ulcerative colitis
  • the present inventors have confirmed that the clinical symptoms and histopathological symptoms caused by inflammatory bowel disease are alleviated and the increase in inflammatory cells in bowels and the production of pro-inflammatory cytokines are suppressed by using a salt of taurodeoxycholic acid, and thus taurodeoxycholic acid and a pharmaceutically acceptable salt thereof can be used as an active ingredient of a pharmaceutical composition for prevention or treatment of inflammatory bowel disease.
  • the present invention includes not only taurodeoxycholic acid represented by Chemical Formula 1 but also pharmaceutically acceptable salts thereof and all possible solvates, hydrates, racemates, or stereoisomers which may be prepared therefrom.
  • Taurodeoxycholic acid represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed from a pharmaceutically acceptable free acid is useful as the salt.
  • Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkandioates, aromatic acids, and aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, hexane-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitro benzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, to
  • the acid addition salt according to the present invention may be prepared by a conventional method, for example, by dissolving taurodeoxycholic acid represented by Chemical Formula 1 in an excessive amount of acid aqueous solution and precipitating this salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile.
  • the acid addition salt may also be prepared by evaporating the solvent or the excess acid from this mixture and drying the residue or by subjecting the precipitated salt to suction filtration.
  • Pharmaceutically acceptable metal salts may be prepared using bases.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt, more specifically it is suitable to prepare a sodium salt as the metal salt.
  • a silver salt corresponding to this is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • the composition is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants which are usually used.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants which are usually used.
  • composition may be administered orally or parenterally and may be administered by transdermal administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, or topical administration when being administered parenterally.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches and the like, and such solid preparations are prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, or gelatin with one or more taurodeoxycholic acids represented by Chemical Formula 1 of the present invention.
  • excipients for example, starch, calcium carbonate, sucrose or lactose, or gelatin
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, oral liquids, emulsions, or syrups and may contain various excipients such as wetting agents, sweetening agents, fragrances, and preservatives in addition to water and liquid paraffin which are commonly used simple diluents.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspension solvents, emulsions, freeze-dried preparations, suppositories, and the like.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable esters such as ethyl oleate, and the like may be used.
  • base for suppositories witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin and the like may be used.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment.
  • the effective dose level may be determined depending on the factors including the type and severity of patient's disease, the activity of the drug, the sensitivity to drugs, the time of administration, the route of administration and rate of excretion, the treatment period, and the drugs used concurrently, and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered singly or multiply. It is important to take into account all of the above factors and administer the composition in an amount so that the maximum effect can be obtained in the minimum amount without side effects, and the amount may be readily determined by those skilled in the art.
  • the effective amount of the compound according to the present invention may vary depending on the age, sex, and body weight of the patient.
  • the compound may be administered daily or every other day in an amount of generally 0.1 mg to 100 mg, specifically 0.1 mg to 50 mg, more specifically 1 mg to 15 mg, even more specifically 2.5 mg to 10 mg per 1 kg of body weight, or the compound may be administered one to three times a day in a total amount of generally 0.1 mg to 100 mg, specifically 0.1 mg to 50 mg, more specifically 1 mg to 15 mg, even more specifically 2.5 mg to 10 mg per 1 kg of body weight.
  • the dose may be increased or decreased depending on the route of administration, severity, sex, body weight, age and the like and does not thus limit the scope of the present invention in any way.
  • the present invention also provides a health functional food for prevention or treatment of inflammatory bowel disease, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides the use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a health food for prevention or improvement of inflammatory bowel disease.
  • taurodeoxycholic acid those isolated from animal carcasses, for example, animals such as sheep, dogs, goats, or rabbits, commercially available ones, and synthesized ones may be all safely used.
  • the taurodeoxycholic acid is a kind of bile acid, is in the form of taurine-conjugated deoxycholic acid, and has a chemical structure represented by [Chemical Formula 1].
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can inhibit the production of pro-inflammatory cytokines, more specifically the production of IL-6, IL-1 ⁇ , or TNF- ⁇ .
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can exhibit an equivalent or higher efficacy as compared with tofacitinib, 5-ASA (5-acetyl salicylic acid), and steroid drugs that are currently used in the clinic for the treatment of ulcerative colitis.
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can decrease the number of inflammatory cells in the bowels.
  • the inflammatory bowel disease may be ulcerative colitis, collagenous colitis, lymphoid colitis, ischemic colitis, convertible colitis, Crohn's disease, Behcet's syndrome, uncertain colitis, hemorrhagic rectal ulcer, or ileal cystitis but is not limited thereto.
  • the present inventors have confirmed that the clinical symptoms and histopathological symptoms caused by inflammatory bowel disease are alleviated and the increase in inflammatory cells in bowels and the production of pro-inflammatory cytokines are suppressed by using a salt of taurodeoxycholic acid, and thus taurodeoxycholic acid and a pharmaceutically acceptable salt thereof can be used as an active ingredient of a health functional food for prevention or improvement of inflammatory bowel disease.
  • taurodeoxycholic acid of the present invention there is no particular limitation on the kind of food to which taurodeoxycholic acid of the present invention is added.
  • Examples of food to which the substances may be added include drinks, meat, sausages, bread, biscuits, rice cakes, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, alcoholic beverages, vitamin complexes, dairy products, and processed dairy products, and the food includes all health functional foods in the usual sense.
  • Taurodeoxycholic acid of the present invention may be added to food as it is or used with other foods or food ingredients, and may be suitably used according to a conventional method.
  • the mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement).
  • the amount of the compound in the health functional food may be 0.1 to 90 parts by weight with respect to the total food weight.
  • the amount may be equal to or less than the above range but the active ingredient may be used in an amount equal to or more than the above range since there is no problem in terms of safety.
  • the health food composition according to the present invention is a beverage composition
  • the beverage composition may contain various flavoring agents or natural carbohydrates as additional ingredients like ordinary beverages.
  • natural carbohydrates include conventional sugars such as monosaccharides, for example, glucose and fructose; disaccharides, for example, maltose and sucrose; and polysaccharides, for example, dextrin and cyclodextrin and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tacmatin, stevia extract (for example, rebaudioside A, glycyrrhizin, and the like) and synthetic flavoring agents (saccharin, aspartame, and the like) may be used advantageously.
  • the proportion of the natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 10 g per 100 of the composition of the present invention.
  • the health food composition according to the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, and the like), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the health food composition may contain natural fruit juice and flesh for the manufacture of fruit juice beverages and vegetable beverages.
  • ingredients may be used independently or in combination.
  • the proportion of these additives is not limited but is generally selected in a range of 0.1 to about 20 parts by weight per 100 parts by weight of taurodeoxycholic acid of the present invention.
  • the present invention also provides a method for preventing or improving inflammatory bowel disease, which includes administering a pharmaceutically effective amount of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.
  • the present invention also provides a method for treating inflammatory bowel disease, which includes administering a pharmaceutically effective amount of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.
  • the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof are the same as those described for the pharmaceutical composition for prevention or treatment of inflammatory bowel disease, and the specific description thereof is as described above.
  • DSS dextran sodium sulfate
  • mice Male C57BL/6 mice (7 to 12 weeks old, body weight of 18 to 30 g) were adapted for one week and used in the experiment. Animal rearing was carried out under the conditions of a temperature of 25° C. and a day and night cycle (12 hours night/12 hours daytime), and feed and drinking water were freely fed. All the animals were managed according to the guidelines for use of experimental animals of Seoul National University IACUC (IACUC: SNU-151223-4-1). On the day of administration of DSS (MP Biomedicals, Santa Ana, Calif., USA) (Day 0), mice were weighed and marked on the tail.
  • DSS MP Biomedicals, Santa Ana, Calif., USA
  • DSS a substance inducing inflammatory bowel disease inducing substance
  • 2% and 5% DSS solutions as an inflammatory bowel disease inducing substance were administrated to male C57BL/6 mice for 7 to 10 days and 4 days, respectively, and then the onset of colitis was monitored by measuring the body weight, stool consistency, and bloody stool. Through monitoring, a 2% DSS solution was used in the experiment.
  • mice Male C57BL/6 mice were fed with a 2% DSS solution together with drinking water from Day 0 of the experiment to induce inflammatory bowel disease.
  • DPBS or 10, 5, 2.5, or 1 mg/kg sodium taurodeoxycholic acid (TDCA) was administered in 0.1 ml by oral gavage one time a day from Day 1 of the experiment.
  • 0.1 ml of 5 mg/kg TDCA was administered one time a day by oral gavage 2 days before DSS administration.
  • the 2% DSS solution was used after being prepared by dissolving DSS powder in sterilized distilled water and filtering the solution.
  • the TDCA was dissolved in DPBS (Dulbecco's phosphate-buffered saline) and used.
  • inflammatory bowel disease was induced by 7-day or repeated administration of 3% or 2.5% DSS solution, and tofacitinib 10 mg/kg, 5-ASA 100 mg/kg or 200 mg/kg, prednisolone 1 mg/kg, and TDCA 2.5 mg/kg were administered one time a day from the start date of DSS administration. From the start date of DSS administration, TDCA 2.5 mg/kg was administered one time a day (QD), two times a day (BID), and three times a day (TID).
  • QD time a day
  • BID two times a day
  • TID three times a day
  • DAI disease activity indexes
  • mice were euthanized with CO 2 and the bowels were excised.
  • the bowels were put in cold 1 ⁇ DPBS and the remaining mesenteric adipose tissue was isolated. At this time, the colon length was measured.
  • the tail end of the colon was opened and wound up with scissors to obtain colon tissue.
  • the obtained colon tissue was fixed in 10% neutral buffered formalin (Sigma-Aldrich, HT501128-4L, St. Louis, Mo., USA) at room temperature for 48 hours and then treated in a tissue processor (Excelsior ES, Thermo scientific, Waltham, Mass., USA) for 12 hours.
  • the processed tissue was sectioned and paraffinized using a microtome (Microm, HM 340E, Thermo Scientific, Waltham, Mass., USA) and an embedding system (HistoStar, Thermo Scientific, Waltham, Mass., USA).
  • a microtome Microm, HM 340E, Thermo Scientific, Waltham, Mass., USA
  • an embedding system HistoStar, Thermo Scientific, Waltham, Mass., USA.
  • the processed tissue was stained with hematoxylin and eosin, and visualized under an optical microscope (Motic, BA310, Redding, Calif., USA) to confirm the histopathological state, and the histopathological state was scored to histological score according to the criteria in the following [Table 2].
  • a colon was obtained from a mouse which had been subjected to an experiment by the same method as that described in ⁇ Example 2>, the peripheral colon was cut into 2 cm in length and the weight was recorded. Next, the colon was chopped into 1 mm pieces and frozen on ice, treated with 500 ⁇ l of cold DPBS containing protease inhibitor (Roche, 11836170001, Basel, Switzerland), and homogenized for 10 to 20 seconds using an electric homogenizer (IKA T10 Basic, Wilmington, SE, USA). The homogenate was centrifuged at 4° C. for 10 minutes at 12,000 ⁇ g to obtain a supernatant.
  • ELISA analysis was performed using the obtained supernatant, IL-6 DuoSet ELISA kit (R & D systems, USA), IL-1 ⁇ DuoSet ELISA kit (R & D systems, USA), and TNF- ⁇ DuoSet ELISA kit (R & D systems, USA) according to the manufacturer's procedure to confirm the production of pro-inflammatory cytokines.
  • a colon tissue was obtained from a mouse which had been subjected to an experiment by the same method as that described in ⁇ Example 2> and put into 30 ml of EDTA and dissociated by being stirred at 37° C. for 30 minutes in order to remove mucus.
  • the tissue was drained with a strainer (70 ⁇ m) and washed with warm DPBS. The washing process was repeated a total of 4 to 5 times.
  • An enzyme mixture was prepared by adding 2.35 ml of RPMI 1640 or DMEM, 100 ⁇ l of enzyme D, 50 ⁇ l of enzyme R, and 12.5 ⁇ l of enzyme A to a gentleMACS C tube (Miltenyi Biotec, 130-096-334, Bergisch Gladbach, Germany).
  • the tissue was transferred to the gentleMACS C tube containing the enzyme mixture and dissociated using the gentleMACS Dissociator (Miltenyi Biotec, 130-093-235, Bergisch Gladbach, Germany). Next, the reaction was conducted at 37° C. for 40 minutes in a thermal incubator (Thermo scientific, BB-15, Waltham, Mass., USA) under continuous rotation using a MACSmix Tube Rotator.
  • the digested cells were resuspended in 4 ml of 40% Percoll solution. To 40% Percoll solution, 4 ml of 75% Percoll solution was added, and centrifugation was conducted at 25° C. and 1200 rpm for 20 minutes.
  • the intermediate layer was recovered and resuspended in 15 ml of complete medium.
  • the resuspended intermediate layer was centrifuged at 4° C. and 1200 rpm for 7 minutes to obtain a pellet, and the pellet was resuspended in 3 ml of complete medium to obtain lamina limba mononuclear cells (LPMC).
  • LPMC lamina limbal mononuclear cells
  • trypan blue exclusion analysis was performed in order to confirm the ratio of viable cells to dead cells. Specifically, 20 ⁇ l of the obtained LPMC was stained with 20 ⁇ l of a 0.4% trypan blue solution. Next, the viable cells were counted to calculate the cell viability. The cell viability was calculated by dividing the number of viable cells by the total number of cells.
  • FACS analysis was performed. Specifically, the obtained LPMC cells were treated with 0.5 ⁇ l of an anti-mouse CD16/CD32 purified monoclonal antibody per 1 ⁇ 10 6 cells at room temperature for 10 minutes in order to block non-specific Fc-mediated interaction. Next, the cells were washed with FACS buffer (1 mM EDTA in 1% FBS and DPBS) and centrifuged at 4° C. and 1200 rpm for 5 minutes. 1 ⁇ 10 6 cells were divided into each FACS tube. Thereto, 0.5 ⁇ l of each primary antibody in 50 ⁇ l of FACS buffer was added, and reaction was conducted at room temperature for 10 minutes.
  • FACS buffer (1 mM EDTA in 1% FBS and DPBS
  • Anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD11b, anti-CD11c, anti-CD45, anti-Ly6c, anti-Ly6g, and anti-MHCII antibodies were used as the primary antibodies.
  • the cells were washed two times with DPBS, resuspended in 200 ⁇ l DAPI, then analyzed using a flow cytometer (LSR Fortessa cytometer, Mississauga, Canada), and graphed.
  • Bone marrow was collected from a DPBS-administered mouse which had been subjected to an experiment by the same method as that described in ⁇ Example 2>, induced to differentiate into macrophages, then pretreated with LPS (10 ng/ml) for 3 hours so as to be 4 ⁇ 10 4 cells in a 96-well plate, treated with TDCA at various concentrations for 1 hour, then treated with ATP (0.5 mM) or BzATP (0.3 mM) for an additional 1 hour, and cultured, and the amount of IL-1 ⁇ in the cell culture was measured and analyzed using an ELISA kit (R & D systems, USA) according to the manufacturer's procedure.
  • TDCA sodium taurodeoxycholic acid
  • mice Female C57BL/6 mice were fed with a 2% DSS solution or DPBS together with drinking water for 10 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 5 mg/kg TDCA was administered to the mice by oral gavage one time a day for 11 days from Day 1 of the experiment, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • DAI change it was confirmed that DAI was high and the inflammation was severe in the DSS+DPBS group. In particular, it was confirmed that 60% (4 out of 6) of mice developed diarrhea and severe bloody stool after 3 to 5 days of DSS administration. On the other hand, it was confirmed that the DAI in the DSS+TDCA group was lower than that in the DSS+DPBS group and the symptoms were alleviated in the DSS+TDCA group ( FIG. 1B ).
  • TDCA 2.5 mg/kg exhibited an effect equivalent to those by tofacitinib 10 mg/kg and 5-ASA 100 mg/kg on inflammatory bowel disease induced by 3% DSS administration for 7 days in terms of the body weight change and DAI change ( FIGS. 9A and 9B ).
  • TDCA alleviates clinical symptoms such as body weight loss, diarrhea, and bloody stool caused by inflammatory bowel disease.
  • mice Female C57BL/6 mice were fed with a 2% DSS solution or DPBS together with drinking water for 7 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 5 mg/kg TDCA was administered to the mice by oral gavage one time a day for 6 days from Day 1 of the experiment, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • the mice were sacrificed on Days 5 and 7 of the experiment by the same method as that described in ⁇ Example 2>, and histopathological symptom analysis was performed.
  • FIGS. 2A to 2C it was confirmed that the colon length remarkably decreased in the DSS and DPBS administration group (DDS+DPBS group) but the decrease in colon length was slight in the DSS and TDCA administration group (DSS+TDCA group) ( FIG. 2A ). It was confirmed that infiltration of inflammatory cells into lamina intestinal, damage to the entire intestinal crypt, and changes in the epithelial surface due to infiltration were observed in the DDS+DPBS group, but in the DSS+TDCA group, epithelial cell defects were not observed similarly to the control group and the infiltration of inflammatory cells into the mucous membrane was slight ( FIG. 2B ). It was confirmed that the average histological score was as high as about 7 and the ulcer was severe in the DDS+DPBS group, but the average histological score was about 4 and the ulcer was alleviated in the DSS+TDCA group ( FIG. 2C ).
  • FIGS. 9C to 9E the colon length and histological lesion index were evaluated in comparison with those by clinical prescription drugs, and as a result, it was confirmed that TDCA 2.5 mg/kg exhibited an effect equivalent to those by tofacitinib 10 mg/kg and 5-ASA 100 mg/kg on inflammatory bowel disease induced by 3% DSS administration for 7 days in terms of the colon length and histological lesion index ( FIGS. 9C, 9D, and 9E ).
  • TDCA alleviates histopathological symptoms such as infiltration of inflammatory cells, damage to colon mucosal epithelial cells, and damage to intestinal crypt caused by inflammatory bowel disease.
  • inflammatory bowel disease In inflammatory bowel disease, the production of pro-inflammatory cytokines such as IL-1, IL-6, TNF- ⁇ , and chemokines increases along with the infiltration of inflammatory cells into intestinal mucosa and lamina intestinal and the production of anti-inflammatory cytokines such as IL-10 is downregulated.
  • pro-inflammatory cytokines such as IL-1, IL-6, TNF- ⁇ , and chemokines
  • mice Female C57BL/6 mice were fed with a 2% DSS solution together with drinking water for 7 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 5 mg/kg TDCA was administered to the mice by oral gavage one time a day for 6 days from Day 1 of the experiment, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • the mice were sacrificed on Day 7 of the experiment by the same method as that described in ⁇ Example 3>, and inflammatory cell and proinflammatory cytokine analysis was performed.
  • FIGS. 3A to 3B it was confirmed that the numbers of CD11b + , Ly6g + , and Ly6c + LPMCs in the colon tissue increased in the DSS+DPBS group but decreased in the DSS+TDCA group ( FIG. 3A ). It was confirmed that IL-6 and IL-1 ⁇ in the colon tissue increased in the DSS+DPBS group but decreased in the DSS+TDCA group ( FIG. 3B ).
  • the concentrations of IL-6, IL-1 ⁇ and TNF- ⁇ in the colon tissue were evaluated in comparison with those by clinical prescription drugs, and as a result, it was confirmed that TDCA 2.5 mg/kg more effectively suppressed the concentration of IL-1 ⁇ than tofacitinib 10 mg/kg and 5-ASA 100 mg/kg, and TDCA 2.5 mg/kg suppressed the concentrations of IL-6 and TNF- ⁇ to the extent equivalent to those by tofacitinib 10 mg/kg and 5-ASA 100 mg/kg in inflammatory bowel disease induced by 3% DSS administration for 7 days ( FIG. 9F ).
  • TDCA suppresses the increase in inflammatory cells and pro-inflammatory cytokines in the bowels by inflammatory bowel disease.
  • mice Female C57BL/6 mice were fed with a 2% DSS solution or DPBS together with drinking water for 10 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 10, 5, 2.5, or 1 mg/kg TDCA was administered to the mice by oral gavage one time a day for 11 days from Day 1 of the experiment, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • histopathological symptom analysis was performed after TDCA was administered to an inflammatory bowel disease-inducing mouse model at various concentrations.
  • mice were fed with a 2% DSS solution or DPBS together with drinking water for 7 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 10, 5, 2.5, or 1 mg/kg TDCA was administered to the mice by oral gavage one time a day for 6 days from Day 1 the experiment, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • mice were sacrificed on Day 8 of the experiment by the same method as that described in ⁇ Example 2>, and histopathological symptom analysis was performed.
  • mice Female C57BL/6 mice were fed with a 2% DSS solution together with drinking water for 7 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 5 mg/kg TDCA was administered to the mice by oral gavage from Day 1 of DSS administration or 2 days before DSS administration, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • mice were sacrificed on Day 8 of the experiment by the same method as that described in ⁇ Example 2>, and the colon length was measured.
  • FIGS. 6A to 6C it was confirmed that the body weight loss rate in the group (DSS+preTDCA group) administered with TDCA before induction of inflammatory bowel disease with DSS was similar to that in the group (DSS+TDCA group) administered with TDCA after induction of inflammatory bowel disease with DSS ( FIG. 6A ). It was confirmed that DAI similarly decreased in both the DSS+preTDCA group and the DSS+TDCA group ( FIG. 6B ). In addition, it was confirmed that the decrease in colon length was suppressed in both the DSS+preTDCA group and the DSS+TDCA group ( FIG. 6C ).
  • TDCA inflammatory cell and pro-inflammatory cytokine analysis was performed after TDCA was administered to an inflammatory bowel disease-induced mouse model before or after induction of inflammatory bowel disease.
  • mice Female C57BL/6 mice were fed with a 2% DSS solution together with drinking water for 7 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>, DPBS or 5 mg/kg TDCA was administered to the mice by oral gavage from Day 1 of DSS administration or 2 days before DSS administration, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • the mice were sacrificed on Day 7 of the experiment by the same method as that described in ⁇ Example 3>, and the inflammatory cell and proinflammatory cytokine analysis was performed.
  • FIGS. 7A to 7B it was confirmed that the numbers of CD11b + , Ly6g + , Ly6c + , CD3 + , CD4 + , CD8 + , CD19 + , and MHCII + CD11c + LPMCs in the colon tissue increased in the DSS+DPBS group but decreased in both the DSS+preTDCA group and the DSS+TDCA group ( FIG. 7A ). It was confirmed that IL-6, IL-1 ⁇ , and TNF- ⁇ in the colon tissue increased in the DSS+DPBS group but decreased in both the DSS+preTDCA group and the DSS+TDCA group ( FIG. 7B ).
  • inflammatory bowel disease was induced in a TGR5 knock-out mouse model, TDCA was administered to the mouse model, and then clinical symptom analysis was performed.
  • mice C57BL/6-Gpbar1 tm1(KOMP)Vlcg mice (TGR5 KO, KOMP Repository, The Knockout Mouse Project, University of California, Davis, Calif.) were used as TGR5 knockout (TGR5 ⁇ / ⁇ ) female C57BL/6 mice.
  • the TGR5 ⁇ / ⁇ female C57BL/6 mice or TGR5 normal (WT) female C57BL/6 mice were fed with a 2% DSS solution or DPBS together with drinking water for 10 days from Day 0 of the experiment by the same method as that described in ⁇ Example 1>.
  • DPBS or 5 mg/kg TDCA was administered to the mice by oral gavage one time a day for 11 days from Day 1 of the experiment, and the body weight and DAI were measured daily.
  • mice freely fed with drinking water were used.
  • DAI change it was confirmed that DAI was high and the inflammation was severe in the DSS+TDCA (TGR5 ⁇ / ⁇ ) group.
  • DAI in the DSS+TDCA (WT) group was lower than those in the other groups and the symptoms were alleviated in the DSS+TDCA (WT) group ( FIG. 8B ).
  • TDCA alleviates clinical symptoms such as body weight loss, diarrhea, and bloody stool caused by inflammatory bowel disease through the mediation of TGR5.
  • the ingredients are powdered, mixed, and then filled in an airtight pouch to prepare a powder.
  • the ingredients are mixed together by a conventional tablet preparing method and then tableted to prepare a tablet.
  • the ingredients are mixed together by a conventional capsule preparing method and then filled into a gelatin capsule to prepare a capsule.
  • the ingredients are mixed together, then 100 mL of 30% ethanol is added to the mixture, this mixture is dried at 60° C. to form granules, and then the granules are filled into a pouch to prepare granules.
  • the ingredients are mixed together and then pills are prepared so as to be 4 g per pill by a conventional pill preparing method.
  • An injection is prepared by mixing the ingredients together so as to be 2 mL per ampoule by a conventional injection preparing method.
  • the ingredients are dissolved in purified water by a conventional liquid formulation preparing method, an appropriate fragrance is added to the solution, and then this solution is filled into a bottle and sterilized to prepare a liquid formulation.
  • taurodeoxycholic acid of the present invention To flour, 0.5 to 5.0 parts by weight of taurodeoxycholic acid of the present invention was added, and bread, cakes, cookies, crackers, and noodles were prepared using this mixture.
  • Meat products for health promotion, noodle soups, and gravies were prepared by adding 0.1 to 5.0 parts by weight of taurodeoxycholic acid of the present invention to soups and gravies.
  • Ground beef for health promotion was prepared by adding 10 parts by weight of taurodeoxycholic acid of the present invention to ground beef.
  • taurodeoxycholic acid of the present invention To milk, 5 to 10 parts by weight of taurodeoxycholic acid of the present invention was added, and various dairy products such as butter and ice cream were prepared using the milk.
  • Brown rice, barley, glutinous rice, and adlay were gelatinized and dried by a known method, and then roasted, and then prepared into a powder having a particle size of 60 mesh using a grinder.
  • Black soybean, black sesame seed, and perilla seed were also steamed and dried by a known method, and then roasted, and then prepared into a powder having a particle size of 60 mesh using a grinder.
  • Taurodeoxycholic acid of the present invention was concentrated under reduced pressure in a vacuum concentrator, sprayed, and dried using a hot air dryer, and the obtained dry product was ground using a grinder to a particle size of 60 mesh to obtain a dry powder.
  • Seonsik was prepared by mixing the grains, seeds, and taurodeoxycholic acid of the present invention prepared above together at the following proportions.
  • Grains (30 parts by weight of brown rice, 15 parts by weight of adlay, 20 parts by weight of barley),
  • Subsidiary materials such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%), and water (75%) and 5 g of taurodeoxycholic acid of the present invention were homogeneously mixed together and sterilized for a short time, and then packaged in a small container such as a glass bottle or a plastic bottle to prepare a health drink.
  • Vegetable juice was prepared by adding 5 g of taurodeoxycholic acid of the present invention to 1,000 ml of tomato or carrot juice.
  • Fruit juice was prepared by adding 1 g of taurodeoxycholic acid of the present invention to 1,000 ml of apple or grape juice.

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EP3915566C0 (en) 2023-11-08
CN112955149A (zh) 2021-06-11
EP3915566B1 (en) 2023-11-08
JP7214273B2 (ja) 2023-01-30
ES2964628T3 (es) 2024-04-08
JP2022508930A (ja) 2022-01-19
EP3915566A1 (en) 2021-12-01

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